Project Summary/Abstract: A growing body of evidence suggests that secondary mitochondrial dysfunction underlies numerous complex diseases including glaucoma. Primary open angle glaucoma (POAG) is the most common form of glaucoma. It represents a group of disorders with population-associated variations in course and severity, which likely signify differences in pathogenesis, some of which may be associated with mitochondrial dysfunction. Mitochondrial haplogroups correspond to maternally-determined geographic populations, and may be protective or confer a higher risk for certain diseases. Utilizing the Primary Open- Angle African-American Glaucoma Genetics database, the PI found worse glaucomatous cupping and more severe visual field loss in the L1c2 haplogroup compared to the closely associated L1b haplogroup despite comparable age, sex, and intraocular pressure (IOP). L1c2 is defined by two missense mutations affecting the mitochondrial gene cytochrome c oxidase I (COI), which encodes a key component of the mitochondrial electron transport/respiratory chain (RC) Complex IV. The RC is the site of ATP synthesis and a primary site for reactive oxygen species generation, disturbances of which have been implicated in glaucoma. In mice with a COI mutation and reduces Complex IV activity, the PI found decreased number of RGCs in male mutants compared to controls, suggesting decreased RC function predisposes to optic neuropathies such as ones resulting from glaucoma. The PI hypothesizes that inherited variations of RC subunits cause impaired mitochondrial respiration, which confers increased susceptibility to RGC loss and to additional stressors like elevated IOP, manifesting as glaucomatous optic neuropathy. Specific aims will: 1) Determine the ocular phenotype and mitochondrial function in a murine model of COI mutation at baseline and in the setting of induced ocular hypertension; and 2) assess the ocular phenotype and mitochondrial function in POAG patients with COI mutations. By optimizing methods of RC functional assessment, this research has the potential to transform the evaluation of cellular respiratory disturbances in glaucoma. Associating disease risks with haplogroup designations constitutes an important step towards individualized glaucoma treatment. The PI will conduct the research under the mentorship of experienced investigators from the University of Pennsylvania (UPenn) and the Children's Hospital of Philadelphia. UPenn is an ideal setting for training clinician-scientists, and the Scheie Eye Institute, in particular, is among the best in the country for research training. The ophthalmology department is committed to fostering success, and has provided the PI with protected time, dedicated space, institutional funds, and a nurturing environment. The PI has mastered multiple techniques included in this proposal and has developed a comprehensive career development plan to facilitate personal growth. By the end of the K award period, the PI will have gained the knowledge needed to mature into an independent investigator who will advance the understanding and treatment of glaucoma.